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Patented July 4, 1950 ORGANOI-ZMETAiJLIC cor/1renacts I METHODS OF MAKING THE SAME tlldouardi-Fmmmeln GenevafJSwit-zerland;assignor a to'sbaboratcirerisapos S. Geneva, f Switzer- .,land;.a.-ocrporation of Switzerland "No"Drawing. Ap'p'lication April 27, 1948, .Serial "No;"23*,611. in switzcrland May.6,'.1947

. val-Claims- 'It iiS :wellflknown that: zcertain cor-garlic chases, notahlywcertain tertiary'land aquaternaryramines rzsuchf-as JacetybchoIine;adrenaline; rhydrastinine, .azemetine, :sephedrine, a morphine, rcodeina-rergotamine, 'idihydroeergotamine, :yohimhine, daisbases and notablyqtherones.which ,possessmhys- -iological properties.willwformxcomplexes ,not.on1y with gold and platinum saltsabutalsonvithrother :metal saltsrsuch as :those. ofv irong nickeldwcobalt, zinc, manganese, cadmium, CODDBInQtQJ- omthe other hand, I have discovered that the said new and generally water-soluble complexes possess the same fundamental physiological properties as the bases from which they are derived but go that their action will last for a much longer time. Effectively, once said complexes are present in the subjects organism, they are decomposed and eliminated much more slowly than simple salts (e. g. chlorides) of the bases considered. This unavoided discovery has a considerable importance in the province of slowly-acting medicines since it makes it possible to lengthen the duration of the physiological effect of certain organic bases such as the ones enumerated hereinbefore by using the new complexes formed by said bases with metal salts rather than said bases themselves.

For instance, I have found that whereas a simple salt of a base remains physiologically effective for about half an hour, after which it is eliminated, the corresponding organo-metallic complex will remain efiective for a much longer time, e. g. several hours. It should be pointed out that with a particular base the stabilisation is variable depending on which metal salt same is combined with.

This invention relates to the said new organometallic compounds, and to a method of producing the same.

.wherein rX-J :is-,.a: :metal of .thegroup -consistingsof manganese, iron .-.-nickel,. cobalt, .zinc, cadmium, (coppemetc, Yisahalqgen, for instance chlorine, aNqeis.nitregen and.R,R.f',.-R' andR' areorganic rresidues.

The method for preparing..,said compounds cccmpr-ises reacting ,a salt containing an ..inorganic anion, e. 2 g. -hydroe-halogenide (preferably: the Ehydroechloride .ofi an -.-0r;ganic.base lwith :zaametal salt which -rsimilarly-rcontains ansinorganic-aniomdor .instance. a-halogenide. and ,prefserablyaacchloride.

organic lbases there :mayhe -cited: acetylcholine, adrenaline, hydrastaline, :emetine, ephedrine, morphine,v codeine, .lerogtamine, dihydro-ergotamine, yohimbine, histamine, quinidine, quinine,;;papaverine, atropine, histidine, priscol, ,privine, etc.

As metal salts there may-bex-znentioned those of manganese,lironflnickel, cobalt, .zinc, cadmium, copper, etc.

Amongst the many organo meta'lliccomplexes having the structure defined hereinbefore the ones that contain manganese are particularly valuable since they are not toxic. In particular, by reacting two molecular weights of acetylcholine hydrochloride with one molecular weight of manganese chloride there is obtained acetylcholine m-angano-chloride which is a new substance possessing the same physiological properties as acetyl-choline but which if used instead of said base will exert its efiect for a much longer time than actually does the base.

How the method according to the invention may be performed will now be explained by way of example in connection with the production of said acetyl-choline mangano-chloride:

0n the one hand 2 gram-molecules (i. e., 363 g.) of anhydrous acetyl-choline hydrochloride are dissolved in 2 litres of alcohol.

On the other hand 1.5 gram-molecules (i. e., 189 g.) of manganese chloride (MnClz) are dissolved in 2 litres of 100% alcohol.

organo-metallic complex is thus obtained which.

cohol and dried in a vacuum." The yielda'mounts to 91% of the theory.

The salt obtained is not hygroscopic; itis hi h soluble in water (colorlesssolution);- almost soluble in 100% alcohol and insoluble in" ether. Its melting point is 157-159 C. Its aqueous solutions remain stable for several r'nonth'sy F As revealed by its complete'analysis' its bulk formula is: i

"and may be written thusz This compound can be injected. Its value from the therapeutic point of "View is considerable since, other factors remainingthe same, its eifects .upon e. g. a rabbit will last nine times longer as the injection of a'g'iven dose'o'f ac'e'tyl-choline will exert its'efiect for'45 minutes, the injection of a dose of the said compoundbontaining the same amount of the acetyl-choline radiclewill exert its efiect for 7 hours.

Acetyl-cholinemangano-chlofid'e" is' not very stable; alkalies willprecipitate"manganese out" Thefollowing references .rfqllsm os t alblat x' .1 9 s reet of German i u ioni u its l.

2. An organo-metallic complex of the formula is filtered out by suction Washed with m rsoluble in water, almost insoluble in 100% alcohol and. insoluble in ether.

' inefthod 'of producing an acetyl-choline manganohalo'genide consisting in reacting two --1r'iolecules 2 or; an 'ac'etylcholine hydrohalogenide ith one moleeul'e of a manganese dihalogenide. v

.' method -of producing acetylcholine man- ..gano-chloride ,.consisting in reacting two mole-' cules ,of- ,acetyl-pholine hydrochloride with one moleculepf manganese dichloride.

""5; A method of producing acetyl-choline mangano-chloride consisting in dissolving two gram- EDOUARD FROMMEL;

gtrtiCtOf eman publication by Gulewitsch.

' jCh'eni; 'Qentralblatt, 1907,11, page 1832, ab-

stra t or German publication by'F. Schmidt.

fill phi" fMonLatshefte V fur Chemie, vol.. .45 (1924), page 633 I M g v v E. J. Fischer WissenschaftlicheQVerOiTentIichungien aus dem siemens-Konzernfvol. 4, pt. II (1925), pp. 172,176, 182, 183. i

Joneset all: Jour. Chem, Soc vol. 52

v Karrerz'Organic{Qhemistryff' (3111i Eng. ed. 1947} page 239." i 

